There have conventionally been developed ointments, poultices, tape-aids, lotions, suppositories, eye lotions and the like in the field of preparations for external use. Among these preparations, percutaneously absorbable preparations have recently attracted public attention and are arousing an increasing interest in themselves. The reasons for this are that in cases where a drug, the pharmacological action of which is expected, is administered locally or systemically so as to be percutaneously absorbed, it is advantageously possible to keep the efficacy of the drug, adjust the rate of absorption thereof easily thereby enabling the prevention of medicinal side effects caused by overdosing the drug, lessen the influence of metabolism exerted by the effect of the drug caused by the initial passage thereof through the liver as is experienced in case of oral administration, thereby enabling the drug to be effectively utilized, and administer comparatively safe even such a drug as to cause liver troubles and the like. In addition to the above preparations, there has now been developed a form of preparation, called "TTS", having a high function to control the release thereof.
(1) In these externally usable preparations attempted to be percutaneously absorbed, it is important to release a drug from a base which contains it, that is, it is necessary for the drug to be efficiently transferred from the base to the skin. To this end, generally importance is placed in the state of dissolution of the drug in the base at the stage of designing these preparations. In other words, how the drug exists in the base will have remarkable effects on not only its physicochemical stability but also its release from the base, percutaneous absorption efficiency and consequent medicinal efficacy. Thus, it comes to be very important when designing preparations, to select a solubilizer which is excellent in solubilization of the drug and exerts an effect on uniform dispersion of the drug into the base.
Solubilizers now used for drugs include fatty acids such as oleic acid and myristic acid, fatty acid esters such as isopropyl myristate and isopropyl palmitate, essence oils such as limonene, peppermint oil and eucalyptus oil, polyhydric alcohols such as polyethylene glycol and propylene glycol, surface-active agents, glycol salicylate and crotamiton, among which crotamiton is frequently used as a solubilizer for difficultly soluble drugs. For example, crotamiton is used as a solubilizer for indomethacin in Japanese Patent Gazette No. Hei 3-3368 (or No. 3368/91), as a solubilizer for steroids in Japanese Pat. Appln. Laid-Open Gazette No. Sho 51-73115 (No. 73115/76) and as a precipitation preventer for valeric acid dexamethasone in Japanese Patent Gazette No. Hei 2-36572. In addition, Japanese Pat. Appln. Laid-Open Gazette No. Sho 59-116212 discloses an indomethacin-containing creamy preparation comprising crotamiton as a solubilizer for the drug.
These solubilizers, however, raise problems as to precipitation of a drug in the crystal form because of shortage of their solubilizability (capability of solubilization), limitation of their use because of their odor, their bleeding with time due to their poor compatibility with the base, and their instability such as their decomposition or discoloration with the lapse of time. Further, these solubilizers cause undesirable side reactions and the like due to their irritation to the skin and they thus exhibit no fully satisfactory results in not a few cases.
(2) On the other hand, absorbability and permeability of the drug are taken as important factors when percutaneously absorbable preparations are designed. This is because the healthy skin is naturally protective against stimuli provided from the outside and, therefore, it makes the absorption and permeation of a drug therethrough comparatively difficult. Accordingly, even if the drug is administered in the form of a percutaneously absorbable preparation, it is difficult at the present to let the drug be absorbed easily through the skin in such an amount as is necessary for fully realizing an intended medicinal efficacy.
Further, in cases where the drugs are administered to let them be absorbed not through the skin but through other biomembranes such as the mouth, rectum, palate, nose or hypoglottis, there are found many drugs which are difficultly permeable or penetrable through the biomembrane concerned depending on the kind of the drugs or which are low in bioavailability.
Thus, there are sought drug-absorption accelerators which fully enhance drugs in permeability, penetrability and absorbability through the skin and other biomembranes, enable the drugs to exhibit their full pharmacological effects in their practical service concentration and are low in local and systemic toxicities and high in usability and safety.
When a drug is attempted to be percutaneously absorbed at the present, there is used an absorption accelerator which enables the drug to be absorbed in a sufficient amount by weakening the barrier function of the stratum corneum where the absorption is to be effected. Of known absorption accelerators, those such as salicylic acid, urea, dimethylsulfoxide and dimethylacetoamide are known for their dissolution of corneum, and, however, the use of them will not necessarily exhibit satisfactory percutaneous absorption of drugs. Propylene glycol, glycerin, pyrrolidone sodium carbonate and the like can keep the corneum humid, but it is hardly appreciated that they are effective in percutaneous absorption of drugs. Further, as absorption accelerators there are known fatty acid esters such as isopropyl myristate and isopropyl adipate, surfactants such as sodium laurylate and polyoxyethylene-sorbitan monolaurate, thioglycerol, urea derivatives or mixtures of a pyrrolidone-based compound and halogenated hydrocarbons (Japanese Pat. Appln. Laid-Open Gazette No. Sho 60-13720), calcium thioglycolate (Japanese Pat. Appln. Laid-Open Gazette No. Sho 60-11431), 1-substituted azacycloalkane-2-one (Japanese Pat. Appln. Laid-Open Gazette No. Sho 60-37092), crotonyl-N-ethyl-o-toluidine (Japanese Pat. Appln. Laid-Open Gazette No. Hei 2-258720) and the like.
Conventional known drug-absorption accelerators, however, are not yet powerful enough to enhance the bioavailability of drugs which are low in permeability and penetrability into the biomembranes, and, thus, they do not provide a practical pharmacological effect in not a few cases. In addition, there are some of conventional absorption accelerators, which themselves exhibit skin irritation and sensitization and present textural discoloration and severe serious side effects due to their successive administration. Furthermore, they are reported to corrode synthetic resins because of their property as a powerful solvent, thereby to elute irritative substances, sensitizers and the like from drug containers, clothing, haberdashery and the like. Under such circumstances, the known absorption accelerators still now leave problems as to practicality such as limitations on general application of the accelerators and method of use thereof.
In view of the above problem (1) as to conventional techniques, a first object of this invention is to provide drug solubilizers having the following excellent characteristics. The solubilizers so provided are such that they make drugs difficult to precipitate with time because of their excellent capability of solubilizing drugs, are physicochemically stable without their decomposition, phase separation and unpleasant odor in the base, are an inactive substance without interaction with the drug and are high in safety because of few side reactions such as skin sensitization.
A second object of this invention is to provide drug-absorption accelerators which can solve the problems (2) as to the conventional techniques. The accelerators so provided are such that they enable drugs to be remarkably enhanced in permeability or penetrability through the skin, are highly safe because of their weak skin irritation and no sensitization and are excellently compatible with the base without giving any change in compatibility between the drug and the base.
Moreover, a third object of this invention is to provide percutaneously absorbable preparations comprising various kinds of drugs and the drug solubilizer of this invention or the drug-absorption accelerator of this invention.